Abstract
Drug-loaded, PEGylated, organic-modified silica (ORMOSIL) nanoparticles prepared by microemulsion condensation of vinyltriethoxysilane (VTES) were investigated as potential nanovectors for cancer therapy. To target cancer stem cells, anti-CD44v6 antibody and hyaluronic acid (HA) were conjugated to amine-functionalized PEGylated ORMOSIL nanoparticles through thiol-maleimide and amide coupling chemistries, respectively. Specific binding and uptake of conjugated nanoparticles were studied on cells overexpressing the CD44v6 receptor. Cytotoxicity was subsequently evaluated in the same cells after the uptake of the nanoparticles. Internalization of nanocarriers loaded with the anticancer drug 3N-cyclopropylmethyl-7-phenyl-pyrrolo- quinolinone (MG2477) into cells resulted in a substantial increase of the cytotoxicity with respect to the free formulation. Targeting with anti-CD44v6 antibodies or HA yielded nanoparticles with similar effectiveness, in their optimized formulation.
Highlights
The risk of developing a cancer has been constantly increasing during the last century
Internalization of nanocarriers loaded with the anticancer drug 3N-cyclopropylmethyl-7-phenyl-pyrrolo- quinolinone (MG2477) into cells resulted in a substantial increase of the cytotoxicity with respect to the free formulation
The surfactant favors the pre-organization of the NP components and monomers, which locate themselves in different NP regions depending on their solvophilicity
Summary
The risk of developing a cancer has been constantly increasing during the last century. Active targeting consists in conjugating nanoparticles with ligands with high binding affinity for specific antigens overexpressed by cancer cells. In several studies this appears to be a more effective approach to ensure or enhance the selective accumulation of the nanosystems in the target tissue [12,13,14,15,16,17,18,19,20]. Low molecular weight HA has been shown to promote cell motility, CD44 cleavage, and angiogenesis [28] This interaction with cancer cells has prompted the conjugation of this biopolymer with several drug-loaded nanoparticles for its use as targeting moiety [25]. Hupetnackee, t[h6e1]u. sHe eonfctea,iltohredunseanoofctaarirloierresdconualndosciagrnriiefircsancotluyldimspigrnovifeictahnetleyffiemctpivreonveessthoef ethffeescetimveonlecsus loefs.these moleHcuelreesi.n, we report the design, synthesis and investigation of a CD44v6-targeting nanocarrier systemHebreaisne,dwoen rmepuoltritfuthnectidoensaigl ns,elsfy-onrtghaensiszeadndORinMveOstSiIgLatnioanoopfaartiCclDes4.4vT6h-teanrgaentoinpgarntiacnleoscawrreireer lsoyasdtemd wbiathsetdheoMn Gm2u4l7t7ifudnructgioonrawl istehlfR-ohrogdaanmiziende BOsRilManOizSeIdL dnearnivoaptaivrtei,ccleosa.teTdhewinthanaodpeanrtsieclPeEs Gw2e00r0e llaoyaedr,eadndwcitohnjtuhgeatMedGw2i4t7h7andarungti-CorD4w4ivth mRohnoodcalmonianleanBtibsioladnyiozerdwidtherHivAa.tiRvees,ucltosadteedmownistthraatedethnaset tPhEeGse20n00anlaoycaer,riearnsdwceorenjsuegleactteidvewlyiitnhtearnnaalinzteid-CbDy4c4evl6ls omvoenreoxcplornesaslinagntihbeoCdyD4o4rv6waitnhd HsigAn.ifiRceasnutltys idnecmreoasnesttrhaetecdytothtoaxt icthiteysoef nthaenotrcaanrsrpieorrstewdedrreugseulepcotinveshlyoritnitnecrunbaalitzieodn tbimy ecse. lls overexpressing the CD44v6 and significantly increase the cytotoxicity of the transported drug upon short incubation 2ti.mMeas.terials and Methods
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